Arachidonic acid (sometimes to be abbreviated as “AA” in the present specification), and eicosanoids, which are products in vivo, have been reported to cause inflammation in the central nervous system and peripheral [non-patent document 1: Science, vol. 294, pages 1871-1875, 2001]. An inhibitor that suppresses arachidonic acid production pathway, and eicosanoid production pathway is promising as a therapeutic drug for inflammatory diseases, and non-steroidal anti-inflammatory drugs such as cyclooxygenase inhibitor and the like have been used as therapeutic drugs for inflammatory pain. However, when a cyclooxygenase inhibitor is used for a long time, digestive tract disorders are sometimes developed as side effects, thus posing a problem. In addition, cardiovascular side effects such as myocardial infarction, cerebral infarction and the like also pose problems in recent years.
Neuroinflammation accompanied by activation of glial cells has been suggested to be a pathological change characteristic of neurodegenerative diseases (e.g., Alzheimer's disease etc.) [non-patent document 2: Molecular Neurobiology (Mol. Neurobiol), vol. 41, pages 115-128, 2010]. It has been reported that anti-inflammatory drugs suppress activation of glial cells and suppress neurodegenerative progression in an animal model of tau overexpression (human variant tau transgenic mouse etc.) which is a pathological characteristic of Alzheimer's disease [non-patent document 3: Neuron, vol. 53, pages 337-351, 2007]. In addition, the effectiveness of suppression of neuroinflammation for the treatment of neurodegenerative diseases such as Alzheimer's disease and the like has been suggested [non-patent document 4: Nature Reviews Neurology (Nat. Rev. Neurol.), vol. 6, pages 193-201, 2010], and a therapeutic drug that suppresses neuroinflammation is promising as a therapeutic or prophylactic drug for neurodegenerative diseases.
Monoacylglycerol lipase (MAGL) is an enzyme that hydrolyzes monoacylglycerol into fatty acid and glycerol. In the central nervous system, the substrate of MAGL is 2-arachidonoylglycerol (also referred to as 2-AG in the present specification) which is degraded to arachidonic acid and glycerol [non-patent document 5: Chemistry and Physics of Lipids (Chem phys Lipids) vol. 121, pages 149-158, 2002]. In recent years, suppression of production of arachidonic acid and eicosanoids, suppression of activation of glial cell, suppression of production of inflammatory cytokine, and a decreasing action on the accumulation of Aβ plaque which is a pathological finding of Alzheimer's disease have been reported in a crossbred animal of MAGL deficient mouse and amyloid R (to be also referred to as Aβ in the present specification) overexpressing animal model (APP/PS1 double transgenic mouse etc.) [non-patent document 6: Cell Report (Cell Rep.), vol. 1, pages 617-623, 2012], and inhibitors etc. that suppress the action of MAGL are promising as a therapeutic or prophylactic drug for Alzheimer's disease.
In addition, as receptors of 2-AG, which is a substrate of MAGL, cannabinoid receptor 1 (to be referred to as CB1 in the present specification), and cannabinoid receptor 2 (to be referred to as CB2 in the present specification) have been identified [non-patent document 7: Biochemical Pharmacology (Biochem. Pharmcol.) vol. 50, 83-90, 1995]. CB1 is mainly expressed in the brain region [non-patent document 8: Molecular Pharmacology (Mol. Pharmacol.), vol. 34, pages 605-613, 1988], and CB2 is expressed in immune cells, and microglial cell in the brain region [non-patent document 9: Neuroscience Letters (Neurosci. Lett.), vol. 396, pages 113-116, 2006]. In recent years, it has been reported that CB1 receptor agonist improves cognitive function [non-patent document 10: Journal of Alzheimer's Disease (J. Alzheimers. Dis.), vol. 30, pages 439-459, 2012], and 2-AG, which is the substrate of MAGL, shows a protective action against neuronal cell death due to Aβ [non-patent document 11: Neuroscience, vol. 178, pages 159-168, 2011]. Therefore, MAGL inhibitor that suppresses degradation of 2-AG is promising as a therapeutic or prophylactic drug that suppresses neuroinflammation, neuronal cell death, Aβ accumulation and the like observed in Alzheimer's disease and having effects on not only symptomatic relief but also disease-modification.
Parkinson's disease, which is one of the neurodegenerative diseases, is a disease associated with movement disorders caused by the degeneration of midbrain substantia nigra dopaminergic neurons, in which activation of glial cell has been reported [non-patent document 12: Annals of Neurology (Ann. Neurol.) vol. 57, pages 168-175, 2005]. While 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine(1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) is known to induce midbrain dopaminergic neuronal cell death in substantia nigra, it has been reported to show a protective action against neuronal cell death in MAGL deficient mice [non-patent document 13: Science, vol. 334, pages 809-813, 2011]. Therefore, inhibitors etc. that suppress the action of MAGL are promising as new therapeutic drugs for Parkinson's disease.
Amyotrophic lateral sclerosis (to be referred to as ALS in the present specification) is a disease associated with degeneration of motor neuron, and an effective treatment method does not exist at present. Activation of glial cell in ALS has been reported [non-patent document 14: Neurobiology of Disease (Neurobiol. Dis.) vol. 15, pages 601-609, 2004]. It has also been reported that activation of CB2 suppresses progression of the disease in mutant superoxide dismutase overexpressing mice as an animal model of ALS [non-patent document 15: European Journal of Pharmacology (Eur. J. Pharmacol.), vol. 542, pages 100-105, 2006]. In addition, it has been reported that MAGL deficient mice are less susceptible to neuoroinflammation due to decreased arachidonic acids, which is an in vivo product of MAGL [non-patent document 13: Science, vol. 334, pages 809-813, 2011]. Therefore, an MAGL inhibitor is promising as a new therapeutic drug for ALS.
Huntington's disease which is one of the neurodegenerative diseases is a disease wherein a neurological function is lost by neuronal cell death and neuroinflammation due to polyglutamine aggregation. It has been reported that activation of CB2 suppresses neuroinflammation and shows a neuroprotective action in R6/2 mice as an animal model of Huntington's disease [non-patent document 16: Brain, vol. 132, pages 3152-3164, 2009]. In addition, it has been reported that MAGL deficient mice are less susceptible to neuoroinflammation due to decreased arachidonic acids, which is a product of MAGL [non-patent document 13: Science, vol. 334, pages 809-813, 2011]. Therefore, an MAGL inhibitor is promising as a new therapeutic drug for Huntington's disease.
2-AG, which is a substrate of MAGL, has been reported to suppress progression of the disease state in an autoimmune encephalomyelitis model, i.e., an animal model of multiple sclerosis which is one of the central demyelination diseases [non-patent document 17: Brain Research (Brain Res.), vol. 1390, pages 126-141, 2011]. In addition, it has been reported that MAGL deficient mice are less susceptible to neuoroinflammation due to decreased arachidonic acids, which is a product of MAGL [non-patent document 13: Science, vol. 334, pages 809-813, 2011]. Therefore, an MAGL inhibitor is promising as a new therapeutic drug for multiple sclerosis.
Traumatic brain injury (TBI) is a condition exerting an extremely harmful influence on the health of individuals, and an effective treatment method does not exist at present. 2-AG, which is a substrate of MAGL, has been reported to have a protective action against neuronal cell death in a closed head injury animal model [non-patent document 18: Nature, vol. 413, pages 527-531, 2001]. Therefore, an MAGL inhibitor is promising as a new therapeutic or prophylactic drug for traumatic brain injury.
Glaucoma most often causes loss of eyesight, and is considered a serious social problem. 2-AG, which is a substrate of MAGL, has been reported to activate aqueous outflow in an intraocular perfusion model [non-patent document 19: Experimental Eye Research (Exp. Eye Res.), vol. 87, pages 106-114, 2008]. Therefore, an MAGL inhibitor is promising as a new therapeutic or prophylactic drug for glaucoma.
Anxiety disorder is a mental disease that occurs highly frequently, and greatly influences the quality of life. 2-AG, which is a substrate of MAGL, has been reported to show an anti-anxiety action in an elevated plus maze test, which is an effective test system of anxiety disorder [non-patent document 20: Behavioural Brain Research (Behav. Brain Res.), vol. 252, pages 10-17, 2013]. Therefore, an MAGL inhibitor is promising as a new therapeutic drug for anxiety disorders.
2-AG, which is a substrate of MAGL, has been reported to show an antinociceptive effect in a formalin test [non-patent document 21: British Journal of Pharmacology, vol. 150, pages 693-701, 2007]. In addition, 2-AG has been reported to show effects in a mechanical hyperalgesia test which is a carcinomatous pain model [non-patent document 22: Pharmacological Research (Pharmacol. Res.), vol. 64, pages 60-67, 2011]. Therefore, an MAGL inhibitor is promising as a new therapeutic drug for inflammatory pain and neuropathic pain.
Epilepsy greatly influences daily life. It is known that neuroinflammation has been induced in the hippocampus of temporal lobe epilepsy patients, and neuroinflammation accompanied by activation of glial cells is involved in convulsive seizure [non-patent document 23: Nature Medicine (Nature Med.), vol. 16, pages 413-419, 2010]. 2-AG, which is a substrate of MAGL, has a suppressive action on pentylenetetrazole-induced convulsive attack, which is an acute convulsion model [non-patent document 24: Neurochemical Research (Neurochem. Res.), vol. 36, pages 1520-1525, 2011]. Therefore, an MAGL inhibitor is promising as a new therapeutic drug for epilepsy.
Depression is a disease that occurs highly frequently in the modern society, and greatly influences the quality of life. 2-AG, which is a substrate of MAGL, has been reported to show an anti-depression action on chronical stress model which is an effective test system of depression [non-patent document 25: Neuropsychopharmacology, vol. 39, pages 1763-1776, 2014]. Therefore, an MAGL inhibitor is promising as a new therapeutic drug for depression.
Migraine is a disease that occurs highly frequently in the modern society, and greatly influences the quality of life. One of the factors that develop migraine is neuroinflammation. Activation of CB2 has been reported to have an analgesic action in nitroglycerin-administered rat, which is an effective test system of migraine [non-patent document 26: Journal of Headache and Pain, vol. 15, No. 14, 2014]. Therefore, an MAGL inhibitor is promising as a new therapeutic drug for migraine.
Cerebral edema is a disease developed in association with various encephalopathies. One of the causes of cerebral edema is collapse of blood-brain barrier. Arachidonic acid and eicosanoids are known to collapse blood-brain barrier [non-patent document 27: Brain Research, vol. 1298, pages 13-23, 2009]. An inhibitor that suppresses the action of MAGL decreases production of arachidonic acid by MAGL. Therefore, an MAGL inhibitor is promising as a new therapeutic drug for cerebral edema.
Cerebral ischemia is one factor causing the onset of cerebral infarction. 2-AG, which is a substrate of MAGL, has been reported to have a brain protective action in a test system for cerebral ischemia [non-patent document 28: Brain Research, vol. 1474, pages 91-99, 2012]. Therefore, an MAGL inhibitor is promising as a new therapeutic drug for cerebral ischemia.
As the heterocyclic compound, the following compounds are known. Patent Document 1 describes that a compound represented by the following formula (I):
wherein each symbol is as defined in patent document 1, is an MAGL inhibitor and useful for the treatment of pain and the like.
Patent Document 2 describes that a compound represented by the following formula (I):
wherein each symbol is as defined in patent document 2, is an MAGL inhibitor and useful for the treatment of pain and the like.
Patent Document 3 describes that a compound represented by the following formula (I):
wherein each symbol is as defined in patent document 3, is an MAGL inhibitor and useful for the treatment of pain and the like.
Patent Document 4 describes that a compound represented by the following formula (I):
wherein each symbol is as defined in patent document 4, is an MAGL inhibitor and useful for the treatment of pain and the like.
Patent Document 5 describes that a compound represented by the following formula:
wherein each symbol is as defined in patent document 5, is useful as an MAGL inhibitor.
Patent Document 6 describes that compounds represented by the following formula:
wherein each symbol is as defined in patent document 6, and the following formula:
wherein each symbol is as defined in patent document 6, are useful as an MAGL inhibitor.
Patent Document 7 describes that a compound represented by the following formula:
wherein each symbol is as defined in patent document 7, is useful as an MAGL inhibitor.
Patent Document 8 describes that a compound represented by the following formula (I):
wherein each symbol is as defined in patent document 8, is an MAGL inhibitor and useful for the treatment, improvement or prophylaxis of metabolic disease (obesity, diabetes).
Patent Document 9 describes that a compound represented by the following formula (I):
wherein each symbol is as defined in patent document 9, is an MAGL inhibitor and useful for the treatment, improvement or prophylaxis of metabolic disease (obesity, diabetes).
Patent Document 10 describes that a compound represented by the following formula (1):
wherein each symbol is as defined in patent document 10, is a p-38α kinase inhibitor and useful for the treatment of inflammation or heart disease.
Patent Document 11 describes that a compound represented by the following formula:
wherein each symbol is as defined in patent document 11, is a TTX-S channel blocker.
Patent Document 12 describes that a compound represented by the following formula:
wherein each symbol is as defined in patent document 12, is an CCR5 antagonist and useful for the treatment of HIV infection.
Patent Document 13 describes that a compound represented by the following formula:
wherein each symbol is as defined in patent document 13, is an MAGL inhibitor and useful for the treatment, improvement or prophylaxis of neurodegenerative disease, anxiety disorder, pain or epilepsy.
In addition, a compound represented by the following formula:
(CAS registry number: 1625094-31-6) is known.